Abstract
Elevated level of palmitic acid (PA), a long-chain saturated fatty acid (SFA), is lipotoxic to many different types of cells including Neuro-2a (N2a) neuroblastoma cells. CD36 is a multifunctional membrane glycoprotein that acts as a fatty acid translocase (FAT) facilitating the transport of long-chain free fatty acids (FFAs) into cells, serves a fatty acid (FA) sensing function in areas including taste buds and the proximal gut, and acts as a scavenger receptor that binds to many ligands, including FAs, collagen, oxidized low-density lipoproteins, and anionic phospholipids. However, the involvement of CD36 in FA uptake and PA lipotoxicity in N2a cells remains unclear. In this study, we examined FA uptake in BSA- and PA-treated N2a cells and investigated the involvement of CD36 in FA uptake and PA lipotoxicity in N2a cells. Our data showed that PA treatment promoted FA uptake in N2a cells, and that treatment with sulfo-N-succinimidyl oleate (SSO), a CD36 inhibitor, significantly decreased FA uptake in BSA- and PA-treated N2a cells, and ameliorated PA-induced decrease of cell viability, decrease of diploid cells, and increase of tetraploid cells. We also found that CD36 knockdown significantly decreased FA uptake in both BSA- and PA-treated cells as compared to their corresponding wild-type controls, and dramatically attenuated PA-induced cell cycle defects in N2a cells. Our data suggest that CD36 may play a critical role in FA uptake and PA lipotoxicity in N2a cells. CD36 may therefore represent a regulatory target against pathologies caused by excess FAs.
Highlights
Circulating levels of free fatty acids (FFAs) are reportedly elevated in obese subjects [1,2], overweight/obese subjects with diabetes mellitus [3], and obese non-alcoholic fatty liver disease (NAFLD) patients [3,4]
In order to examine whether CD36-mediated FA uptake was required for palmitic acid (PA) lipotoxicity, we first investigated the effects of PA treatment on CD36 expression
N2a cells were treated with 200 μM PA or bovine serum albumin (BSA) control for 0.5, 1, 2, 4, or 6 h, and FA uptake was analyzed by incubation with 15 μM 4,4-Difluoro-5,7-Dimethyl-4-Bora-3a,4a-Diaza-sIndacene-3-Dodecanoic Acid (BODIPYTM FL C12), a widely used fluorescent long-chain
Summary
Circulating levels of free fatty acids (FFAs) are reportedly elevated in obese subjects [1,2], overweight/obese subjects with diabetes mellitus [3], and obese non-alcoholic fatty liver disease (NAFLD) patients [3,4]. Excessive level of palmitic acid (PA), a long-chain saturated fatty acid (SFA), has been shown to induce lipotoxicity in many types of cells including skeletal muscles, liver cells, neuronal cells, neuroblastoma, and microglia cells [5,6,7,8,9,10,11]. Stress in different cells including H9C2 cardiomyocytes [14], skeletal muscle cells [14,15], pancreatic β cells [16], and hypothalamic neurons [17] while N-acetyl cysteine, an antioxidant, and 4-phenylbutyrate, an inhibitor of ER stress, are not able to alleviate PA-induced decrease of cell viability in neuroblastoma Neuro-2a (N2a) cells [9]. Fatty acyl-CoA may be catabolized to generate energy or anabolized to produce a range of molecules such as second messengers, hormones, and diacylglycerols [21]
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